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CEA-, Her2/Neu-, BCRP- and Hsp27-Positive Microparticles in Breast Cancer Patients*

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CEA-, Her2/Neu-, BCRP- and Hsp27-Positive Microparticles in Breast Cancer Patients* ANTICANCER RESEARCH 30: 1707-1712 (2010) CEA-, Her2/neu-, BCRP- and Hsp27-positive Microparticles in Breast Cancer Patients* SUSANNE LIEBHARDT1, NINA DITSCH1, RIENK NIEUWLAND2, ANDREAS RANK3, UDO JESCHKE4, FRANZ VON KOCH5, KLAUS FRIESE1 and BETTINA TOTH6 1Department of Obstetrics and Gynecology - Großhadern, and 3Department of Internal Medicine III – Großhadern, Ludwig Maximilians University, 81377 Munich, Germany; 2Department of Clinical Chemistry, Academic Medical Center 1105 AZ Amsterdam, the Netherlands; 4Department of Obstetrics and Gynecology – Maistrasse, Ludwig Maximilians University, 80337 Munich, Germany; 5Department of Obstetrics and Gynecology, Klinikum Oritter Orden, 80638 Munich, Germany; 6Department of Gynecological Endocrinology and Reproductive Medicine, Ruprecht Karls University, 69115 Heidelberg, Germany Abstract. Background: This is the first prospective case- So far, the only serum tumour markers for breast cancer are control study that evaluates the expression of tumour-specific cancer antigen (CA) 15-3 and carcinoembryonic antigen antigens on circulating microparticles (MP) in breast cancer (CEA). Neither marker is used in diagnosis of primary breast patients and in women with benign breast tumour. Materials cancer but only to diagnose recurrent disease and to evaluate and Methods: MP were determined by flow cytometry in response to chemotherapy (1). Prognostic factors for breast patients with breast cancer (n=34; T1 (n=19) and T2 (n=15)) cancer are the status of axillary lymph nodes, age, tumour and women with benign breast tumour (n=19). Results: load and histological parameters (2), urokinase-type Patients with lymph node metastases (N1, n=9) showed plasminogen activator (uPA) and its inhibitor (PAI-1) (3), significantly higher numbers of annexin V+ MP (p=0.042), and the presence of bone marrow micrometastases (4). CD66+ MP (p=0.045), BCRP1+ MP (breast cancer resistance Several investigators have demonstrated elevated protein) (p=0.025) and Hsp27+ MP (p=0.034) than controls. concentrations of circulating microparticles (MPs) in breast Furthermore, T1 patients had significantly higher levels of cancer patients (5-7). MPs are cellular membrane vesicles of annexin V+ MP (p=0.004), CD66+ MP (p=0.025), BCRP1+ a size between 0.1 and 1.0 μm, which are shed into the MP (p=0.008) and Hsp27+ MP (p=0.02) than controls. plasma during cell activation and apoptosis. (8) MPs are Conclusion: Significant differences are present between breast present in the plasma of healthy humans, where they cancer patients with lymph node metastases and controls originate mainly from platelets, followed by endothelial concerning annexin V-, CD66-, BCRP1- and Hsp27-positive cells, granulocytes and erythrocytes. (9) Increased plasma MP. To specify the role of these MP subpopulations in breast concentrations of MPs have been reported in vascular cancer progression, further studies enrolling larger patient diseases, diabetes and severe trauma (10) and in several types groups are part of ongoing research. of cancer including gastric (11), lung (12), and colorectal cancer (13), leukaemia (14), myeloproliferative disorders (15), pancreatic (5) and breast cancer (5-7). In patients with prostate cancer, high platelet-derived MP (PMP) is correlated *This work contains parts of the doctoral theses of Kerstin Steinig with short overall survival. (16) MP promote tumour growth, and Susanne Liebhardt. spreading and tumour-induced neovascularization (11). There are several antigens which have been identified on Correspondence to: Susanne Liebhardt, Department of Obstetrics breast cancer tissue: cluster of differentiation 66 (CD66), and Gynecology – Großhadern, Ludwig Maximilians University, Marchioninistr. 15, D-81377 Munich, Germany. Tel: +49 8970952856, human epidermal growth factor receptor 2 (Her2/neu), breast Fax: +49 8970955854, e-mail: [email protected] cancer resistance protein (BRCP) and heat-shock protein 27 (Hsp27). CD66 is known as the CEA (carcinoembryonic Key Words: CEA, Her2/neu, BCRP, HSP27, microparticles. antigen) family of molecules (1) and plays a role in cell 0250-7005/2010 $2.00+.40 1707 ANTICANCER RESEARCH 30: 1707-1712 (2010) adhesion and rejection processes and therefore in tumour and IgG-PE were from Immuno Quality Products (Groningen, growth and spreading (1, 17). Elevated levels of CEA occur in Netherlands) and IgG-FITC from Immunotech (Marseille, France). patients with colorectal carcinoma (18), but also in patients Anti-CD66-PE (detecting CD66c, e) and anti-Her2/neu-PE were from BD Biosciences Pharmingen (San Jose, USA), anti-BCRP1- with breast, lung, ovarian, prostate, hepatocellular and FITC from Chemicon International (Billerica, USA) and anti- pancreatic cancer (19). Her2/neu, a transmembrane Hsp27-FITC from Stressgen (Victoria, Canada). All antibodies and glycoprotein from the epidermal growth factor receptor family annexin V were diluted with phosphate-buffered saline (PBS; 154 (EGFR) (20, 21), is expressed by various epithelial tissues. mmol/l NaCl, 1.4 mmol/l phosphate, pH 7.4). Final dilutions were: Her2/neu is overexpressed in 10-31% of invasive breast annexin V-FITC 1:100 (v/v), annexin V-PE 1:200, IgG-PE 1:10, cancers, where it is a marker of poor prognosis (22-24). BCRP, IgG-FITC 1:10, anti-Her2/neu-PE 1:2, BCRP1-FITC 1:5, Hsp27- a 72 kDa plasma membrane protein from the ABC (ATP FITC 1:5, anti-CD66-PE was used undiluted. Isolation and identification of MP were performed as described binding cassette) transporter family (25), was first discovered in by Nieuwland (30). In brief, frozen plasma (250 μl) was thawed doxorubicin-resistant breast cancer cells (26). Endogenous slowly on melting ice for approximately one hour. After BCRP expression is found in placenta, liver, bowel, ovary, centrifugation at 17570×g and 20˚C for 30 minutes, 225 μl of MP- blood vessels and in the ductuli and lobuli of the breast (27). free supernatant was taken off. The remaining MP pellet was diluted Heat-shock proteins mediate protein transport and folding and with 225 μl of PBS containing 10.9 mmol/l trisodium citrate are cytoprotective. (28) Hsp27 belongs to the family of small (PBS/citrate buffer), re-suspended and centrifuged again for 30 Hsps (15-30 kDa) (28). An overexpression of Hsp27 is found minutes at 17570×g and 20˚C. Afterwards the supernatant (225 μl) was removed, 75 μl of PBS/citrate buffer was added, and the MP in various carcinomas like breast, ovarian, colorectal, pellet was resuspended again. Five μl of the MP suspension was hepatocellular, kidney, lung and prostate carcinoma (29). diluted in 35 μl CaCl2 (2.5 mmol/l)-containing PBS. For MP The aim of our prospective case–control study was to staining, 5 μl APC-labelled annexin V and 5 μl of a cell-specific detect tumour-specific MPs in women with breast cancer. monoclonal antibody or isotype-matched control antibodies were Therefore, MP-expressing CD66, Her2/neu, BCRP and added to the specimen. For detection of tumour-specific MP, Hsp27 were evaluated in breast cancer patients using women antibodies against Her2/neu, BCRP, CD66 and Hsp27 were used. with benign breast tumours well as controls. Samples were incubated in the dark for 15 minutes at room temperature. The reaction in all samples was stopped with 900 μl calcium buffer (2.5 mmol/l), except for the annexin V control, where Patients and Methods citrate-containing PBS (900 μl) was added. MP were analysed in a FACScan flow cytometer (Becton Study population. Newly diagnosed patients with histologically Dickinson, Heidelberg, Germany) using Cell Quest Software (Becton proven breast cancer (n=34) were included in the study before Dickinson, San Jose, CA, USA). Forward scatter (FSC) and side surgical treatment or neoadjuvant chemotherapy and classified scatter (SSC) were set at a logarithmic gain. MPs were identified on according to the TNM system: 19 patients had tumours <2 cm (T1) basis of their size and density and their capacity to bind to a cell- and 15 had tumours of a size between 2 and 4 cm (T2). 23 patients specific monoclonal antibody and annexin V. Cell-specific labelling had negative axillary lymph nodes (N0), 9 had positive lymph nodes with monoclonal antibodies was corrected for identical concentrations (N1) and in 2 patients the nodal state was unknown (Nx). Women of isotype-matched control antibodies and annexin V measurements with a benign breast tumour (n=19) were included in the control were corrected for autofluorescence. The concentration of MPs per group before core biopsy of breast tumours which had been detected litre of plasma was estimated according to Berckmans (9). during routine mammography. Neither patients nor controls smoked or were taking oral contraceptives or hormonal treatment. Patients Statistics. Parametrically distributed data were expressed as with the confounding factors hypertension, history of cancer or mean±standard deviation (SD) (minimum-maximum). All other data thrombosis, aspirin or low molecular weight heparin (LMWH) were presented as the median (Q1-Q3=interquartile range). treatment were excluded. All patients were Caucasians. Signed Independent variables were analyzed by Mann-Whitney-U-test, all informed consent was obtained from all participants, allowing others by using Chi-square and Fisher’s exact test. P-values <0.05 analysis of all clinical and laboratory data mentioned in this paper. were regarded as statistically significant. Data were examined with The Human Investigation Review Board of the Ludwig Maximilians SPSS (SPSS,
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